The outbred SENCAR stock of mice has been a useful model for dissecting out the multistage nature of cancer development as well as the critical mechanisms involved in skin tumorigenesis. More recently several inbred strains derived from the SENCAR stock have been developed. These strains display different sensitivities to two-stage carcinogenesis and, in particular, some of them show a dissociation between the susceptibility to papilloma development and their malignant conversion into Squamous Cell Carcinomas (SCC). Interestingly we have recently shown that the treatment of young SENCARB/Pt mice with N-methyl-N-nitrosourea (MNU) results in the induction of a high incidence (> 90 percent) of thymic lymphomas occurring between 4 and 6 months after MNU injection. In contrast SSIN mice were not susceptible to MNU induced thymic lymphomas supporting the idea that the differential susceptibility to chemical carcinogenesis between SSIN and SENCARB/Pt is not restricted to the skin model and therefore, these strains constitute a powerful tool for the mechanistic studies of the underlying genetic basis of resistance and susceptibility to chemical carcinogenesis. Specific Aim 1: To establish a genetic mode or the susceptibility to chemically induced thymic lymphomas using SSIN (resistant) and SENCARB/Pt (susceptible) strains. The long-term objective of this project is to identify the putative resistance/susceptibility gene/s that play a role in the differential behavior against chemical carcinogenesis in these two SENCAR-derived inbred strains and investigate their possible mechanisms of action. Using a backcross we have previously identified a region on mouse chromosome 14 containing a putative susceptibility gene for skin tumor progression. We are now proposing to use the lymphoma model to investigate whether lymphoma susceptibility is controlled by the same locus and follows the same genetic models than that observed in the skin model. Specific Aim 2: To identify the gene/s involved in the differential susceptibility to MNU carcinogenesis by positional cloning. We will develop a high-resolution linkage map and a physical map of the region/s harboring gene/s involved in MNU-induced thymic lymphoma susceptibility using intercross mice between the wild derived MBT/Pas strain and SENCARB/Pt. We will continue with approaches to isolate at least the more relevant gene by positional cloning, and positional candidate routes. Specific Aim 3: To investigate the extent of the susceptibility of SENCARB/Pt to environmental carcinogens. So far, we have shown differences in susceptibility in lymphomas and progression of skin cancer. The purpose of this specific aim is to investigate if SENCARB/Pt mice have also a higher susceptibility to chemically induced mammary carcinomas and UV induced skin carcinomas. Specific Aim 4: To investigate whether genomic instability plays a major role in the phenotypic differences between SSIN and SENCARB/Pt strains against chemical carcinogenesis. We have the hypothesis that the differences in susceptibility to chemical carcinogenesis between these strains are related to the different levels of genomic instability displayed. Using a new PCP technique we will be able to evaluate the degree of genomic instability and if this hypothesis is substantiated we will investigate probable mechanisms involved in this phenomena.